Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. Metastatic disease is primarily, but not uniquely, associated with malignant tumor cells and infections.
Cancer occurs after a single cell in a tissue is genetically damaged in ways that result in the formation of a putative cancer stem cell possessing a malignant phenotype. These cancer stem cells are able to undergo uncontrolled abnormal mitosis, which serves to increase the total number of cancer cells at that location. When the area of cancer cells at the originating site become clinically detectable, it is called primary tumor. Some cancer cells also acquire the ability to penetrate and infiltrate surrounding normal tissues in the local area, forming a new tumor. The newly formed tumor in the adjacent site within the tissue is called a local metastasis.
Some cancer cells acquire the ability to penetrate the walls of lymphatic and/or blood vessels, after which they are able to circulate through the bloodstream (circulating tumor cells) to other sites and tissues in the body. This process is known (respectively) as lymphatic or hematogenous spread. After the tumor cells come to rest at another site, they re-penetrate through the vessel or walls (extravasion), continue to multiply, and eventually another clinically detectable tumor is formed. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of the hallmarks of malignancy. Most tumors and other neoplasms can metastasize, although in varying degrees (e.g., basal cell carcinoma rarely metastasizes).
Metastatic tumors are very common in the late stages of cancer. The most common places for the metastases to occur are the lungs, liver, brain, and the bones. There is also a propensity for certain tumors to seed in particular organs. For example, prostate cancer and breast cancer usually metastasizes to the bones. Colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasizes to the ovaries in women. Studies have suggested that these tissue-selective metastases processes are due to specific anatomic and mechanical routes. In particular, a cancer cell may colonize other organs and progress into macroscopic lesions only if its genotypic and phenotypic features are somehow compatible with the local microenvironment. Thus, the identification of the molecular determinants underpinning cancer cells colonization of secondary organs may reveal novel therapeutic targets to effectively counteract metastatic disease.
Prostate cancer develops in the prostate, a gland in the male reproductive system, and often affects men over the age of fifty. Prostate cancer is most common in the developed world, with increasing rates in the developing world. Globally, it is the sixth leading cause of cancer-related death in men, but it is the first in the United Kingdom and the second in the U.S. However, many men with prostate cancer never develop symptoms, do not undergo therapy, and eventually die of other unrelated causes. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.
Most prostate cancers are slow growing: but there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Chemotherapy has been widely used for prostate cancer treatments. Recent studies have focused on chemotherapy-induced apoptosis of tumor cells to inhibit tumor cell growth and promote cell death.
Two important molecular targets for prostate cancer treatment include prostate tissue secreted growth factors, such as transforming growth factor type-P (TGF-P) and prostate-specific antigen (PSA). TGF-P regulates cell growth, differentiation, and development of a variety of functions. PSA, a chymotrypsin-like serine protease known as gamma-seminoprotein or human glandular kallikrein-related peptidase-3 (KLK3), is secreted from epithelial prostate tissue, where it is highly localized. PSA screening has been used to identify individuals with prostate cancer. However, PSA is an indicator of not only prostate cancer, but also prostatitis or benign prostatic hyperplasia. In fact, only 30% with high PSA have prostate cancer diagnosed after biopsy. Although therapies targeting the androgen receptor, an upstream regulator of PSA, have been effective in treating prostate cancer, the disease state sometimes progresses and results in castrate-resistant prostate cancer (CRPC). The androgen receptor (AR) is widely thought to play a vital role also in the disseminated CRPC, which affects primarily the skeleton.
Interleukin-1 beta (IL1β; SEQ ID NO: 1 for IL-1β precursor and SEQ ID NO:2 for cleaved mature IL-1β), also known as catabolin, is a cytokine protein, which in humans is encoded by the IL1B gene. IL1β is a member of the interleukin 1 cytokine family and produced by activated macrophages as a pro-protein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). This cytokine is an important mediator of the inflammatory response, and involved in cellular activities including cell proliferation, differentiation, and apoptosis. Studies associate the gene with susceptibility to schizophrenia.
There is a need in the art to develop novel methods of treatment that avoid, delay or minimize the development of metastatic tumors in a subject, especially in the context of metastatic bone cancer associated with primary prostate cancers. The present invention fulfills this need.